Anaemia is independently associated with mortality in patients with hepatocellular carcinoma.

BACKGROUND: Anaemia is frequent in patients with cancer and/or liver cirrhosis and is associated with impaired quality of life. Here, we investigated the impact of anaemia on overall survival (OS) and clinical characteristics in patients with hepatocellular carcinoma (HCC). MATERIALS AND METHODS: HCC patients treated between 1992 and 2018 at the Medical University of Vienna were retrospectively analysed. Anaemia was defined as haemoglobin level <13 g/dl in men and <12 g/dl in women. RESULTS: Of 1262 assessable patients, 555 (44.0%) had anaemia. The main aetiologies of HCC were alcohol-related liver disease (n = 502; 39.8%) and chronic hepatitis C (n = 375; 29.7%). Anaemia was significantly associated with impaired liver function, portal hypertension, more advanced Barcelona Clinic Liver Cancer stage and elevated C-reactive protein (CRP). In univariable analysis, anaemia was significantly associated with shorter median OS [9.5 months, 95% confidence interval (95% CI) 7.3-11.6 months] versus patients without anaemia (21.5 months, 95% CI 18.3-24.7 months) (P < 0.001). In multivariable analysis adjusted for age, Model for End-stage Liver Disease, number of tumour nodules, size of the largest nodule, macrovascular invasion, extrahepatic spread, first treatment line, alpha-fetoprotein and CRP, anaemia remained an independent predictor of mortality (adjusted hazard ratio 1.23, 95% CI 1.06-1.43, P = 0.006). CONCLUSIONS: Anaemia was significantly associated with mortality in HCC patients, independent of established liver- and tumour-related prognostic factors. Whether adequate management of anaemia can improve outcome of HCC patients needs further evaluation.

Clinical characteristics and outcome of patients with combined hepatocellular-cholangiocarcinoma-a European multicenter cohort.

BACKGROUND: There is no clear consensus on the optimal systemic treatment regimen in combined hepatocellular-cholangiocarcinoma (cHCC-CCA) patients. We describe clinical characteristics and outcome of cHCC-CCA patients, with a special focus on patients receiving palliative systemic therapy, including immune checkpoint inhibitors (ICIs). METHODS: In this European retrospective, multicenter study, patients with histologically proven cHCC-CCA treated at four institutions between April 2003 and June 2022 were included. In patients receiving palliative systemic therapy, outcome was compared between cytotoxic chemotherapy (CHT)- and non-cytotoxic CHT (nCHT)-treated patients. RESULTS: Of 101 patients, the majority were male (n = 70, 69%) with a mean age of 64.6 ± 10.6 years. Only type of first-line treatment was independently associated with overall survival (OS). Palliative systemic therapy was administered to 44 (44%) patients. Of those, 25 (57%) patients received CHT and 19 (43%) had nCHT (n = 16 of them sorafenib) in systemic first line. Although there was no significant difference in overall response rate (ORR; CHT versus nCHT: 8% versus 5%), disease control rate (24% versus 21%), and median progression-free survival {3.0 months [95% confidence interval (CI) 1.4-4.6 months] versus 3.2 months (95% CI 2.8-3.6 months), P = 0.725}, there was a trend towards longer median OS in the CHT group [15.5 months (95% CI 8.0-23.0 months) versus 5.3 months (95% CI 0-12.5 months), P = 0.052]. However, in multivariable analysis, type of first-line regimen (CHT versus sorafenib) was not associated with OS. ORR in patients receiving ICIs (n = 7) was 29%. CONCLUSIONS: In patients with cHCC-CCA, OS, progression-free survival, ORR, and disease control rate were not significantly different between individuals receiving CHT and patients receiving nCHT. Immunotherapy may be effective in a subset of patients. Prospective studies are needed to identify optimal systemic treatment regimens in cHCC-CCA.

Cancer and hepatic steatosis.

Non-alcoholic fatty liver disease (NAFLD) is a highly prevalent and increasing liver disease, which encompasses a variety of liver diseases of different severity. NAFLD can lead to liver cirrhosis with all its complications as well as hepatocellular carcinoma (HCC). Steatosis of the liver is not only related to obesity and other metabolic risk factors, but can also be caused by several drugs, including certain cytotoxic chemotherapeutic agents. In patients undergoing liver surgery, hepatic steatosis is associated with an increased risk of post-operative morbidity and mortality. This review paper summarizes implications of hepatic steatosis on the management of patients with cancer. Specifically, we discuss the epidemiological trends, pathophysiological mechanisms, and management of NAFLD, and its role as a leading cause of liver cancer. We elaborate on factors promoting immunosuppression in patients with NAFLD-related HCC and how this may affect the efficacy of immunotherapy. We also summarize the mechanisms and clinical course of chemotherapy-induced acute steatohepatitis (CASH) and its implications on cancer treatment, especially in patients undergoing liver resection.

Non-selective ß-blockers improve the correlation of liver stiffness and portal pressure in advanced cirrhosis.

BACKGROUND: Liver stiffness (LS) correlates with portal pressure (hepatic venous pressure gradient, HVPG). However, the dynamic components of portal hypertension (PHT) in advanced cirrhosis may not be adequately assessed by TE. The influence of treatment with non-selective ß-blockers (NSBB) on the correlation of HVPG and LS has not been investigated. METHODS: One hundred and twenty-two patients with esophageal varices were included. LS, hemodynamic parameters, and HVPG were recorded at baseline (BL) and after 6 weeks of treatment with NSBB (FU). The correlation of LS and HVPG was compared to control patients with HVPG ≤ 12 mmHg. RESULTS: Patients with higher Child-Pugh stages (A:88/B:25/C:9) had higher levels of liver stiffness (47.4 ± 16.5 vs. 70.3 ± 7.9 vs. 73.7 ± 2.1 kPa) and HVPG (21 ± 5 vs. 26 ± 5 vs. 26 ± 4 mmHg). The correlation of LS and HVPG was stronger in controls with HVPG ≤ 12 mmHg (R = 0.951; P < 0.0001) than in patients with HVPG > 12 mmHg (R = 0.538; P = 0.0004). The association of HVPG with LS became stronger under treatment with NSBB, which finally restored the linear correlation of HVPG and LS (R = 0.930; P < 0.0001). Forty-three percent (53/122) of patients were hemodynamic responders to NSBB. The improvement in the correlation of LS and HVPG under NSBB was mainly noted in hemodynamic responders (R = 0.864), but not in nonresponders (R = 0.535), whereas changes in LS, heart rate, and MAP were similar in responders and nonresponders. CONCLUSIONS: Targeting the hyperdynamic circulation and the increased splanchnic blood inflow by treatment with NSBB unmasks the linear (mechanical) correlation of HVPG and LS in patients with HVPG > 12 mmHg. Measurement of LS by TE is not a feasible method to assess the dynamic components of PHT.

The effects of sorafenib on the portal hypertensive syndrome in patients with liver cirrhosis and hepatocellular carcinoma--a pilot study.

BACKGROUND: Increased intrahepatic vascular resistance and hyperperfusion in the splanchnic circulation are the principal mechanisms leading to portal hypertension in cirrhosis. Several preclinical studies have demonstrated a beneficial effect of the multikinase inhibitor sorafenib on the portal hypertensive syndrome. AIM: To investigate the effect of sorafenib on hepatic venous pressure gradient (HVPG), systemic hemodynamics and intrahepatic mRNA expression of proangiogenic, profibrogenic and proinflammatory genes. METHODS: Patients with liver fibrosis/cirrhosis and hepatocellular carcinoma were treated with sorafenib 400 mg b.d. HVPG measurement and transjugular liver biopsy were performed at baseline and at week 2. Changes in HVPG and intrahepatic mRNA expression of vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), RhoA, tumour necrosis factor-alpha (TNF-α) and placental growth factor (PlGF) were evaluated. RESULTS: Thirteen patients (m/f = 12/1; Child-Pugh class A/B = 10/3) were included. The most common aetiology of liver disease was alcohol consumption (n = 7). Eleven patients had an elevated portal pressure, including eight patients with clinically significant portal hypertension. A significant decrease of HVPG (≥ 20% from baseline) was observed in four subjects. In HVPG responders, we observed mRNA downregulation of VEGF, PDGF, PlGF, RhoA kinase and TNF-α, while no substantial mRNA decrease was found in nonresponders in any of the five genes. In two of the four HVPG responders we observed a dramatic (43-85%) mRNA decrease of all five investigated genes. CONCLUSION: Larger controlled clinical trials are needed to demonstrate any potential beneficial effect of sorafenib on portal hypertension in patients with cirrhosis.

Prognostic factors in patients with advanced hepatocellular carcinoma treated with sorafenib.

BACKGROUND: Sorafenib is the new reference standard for patients with advanced hepatocellular carcinoma (HCC). AIM: To identify prognostic factors in sorafenib-treated HCC patients and to evaluate outcomes with respect to liver function. METHODS: In this retrospective study, 148 HCC patients received sorafenib 400 mg b.d. across 11 Austrian institutions. Seventy-eight HCC patients who received best supportive care (BSC) in the pre-sorafenib era served as a control. RESULTS: In sorafenib-treated patients, low baseline α-fetoprotein, low Child-Pugh (CP) score, compensated cirrhosis, and low baseline aspartate aminotransferase (AST) were associated with significantly longer overall survival (OS) on univariate analysis. CP score and baseline AST remained independent prognostic factors on multivariate analysis. In patients with Barcelona Clinic liver Cancer (BCLC) stage B or C HCC (sorafenib: n = 139; BSC: n = 39), CP-A patients had a median OS of 11.3 (sorafenib [n = 76]) vs. 6.4 (BSC [n = 17]) months (P = 0.010), and CP-B patients had a median OS of 5.5 (sorafenib [n = 55]) vs. 1.9 (BSC [n = 22]) months (P = 0.021). In the sorafenib group, median OS according to baseline AST was 11.8 (<100 U/L [n = 58]) vs. 3.9 (≥100 U/L [n = 15]) months for CP-A patients (P = 0.127), and 6.5 (<100 U/L [n = 33]) vs. 2.1 (≥100 U/L [n = 21]) months for CP-B patients (P = 0.011). There was no survival difference between sorafenib and BSC in patients with BCLC stage D HCC (1.5 vs. 1.4 months; P = 0.116). CONCLUSIONS: Sorafenib was associated with improved survival in both CP-A and CP-B patients. In CP-B patients, baseline AST may be helpful in determining which patients are most likely to benefit from sorafenib.

[Inflammatory bowel disease--familial and sporadic form]. / Idiopatické strevní zánety--familiární a sporadická forma.

THE AIM: The aim of this thesis was to elucidate more differences between a familial and sporadic inflammatory bowel disease by comparing certain clinical data. METHODS: We assessed 248 patients with inflammatory bowel disease (IBD) observed in 1994-2004 in the Academic Department of Gastroenterology at the Medical Faculty in Hradec Králové. To get information about the defined characters we obtained from the questionary and the hospital data. RESULTS: We did not identify any relationship between the onset of the disease and a certain age group, yet males seem to be more prone to familial Crohn's disease. The more frequent familial form of Crohn's disease was the fibro-stenotic one. There were no differences in the onset of the disease. We did not prove the differences in extraintestinal signs, alergy and comorbidities. We did not find any differences in therapy response in relation to the type of nutrition (enteral, parenteral) and the administration of immunosupresive drugs. The biological therapy in sporadic and familial Crohn's disease did not differ either. Surgical intervention was more frequent in Crohn's patients compared to the patients with ulcerative colitis; yet no difference was identified between familial and sporadic cases. Appendectomy carried out before the onset of the disease was later diagnosed as Crohn's disease in more instances than ulcerative colitis. CONCLUSION: We did not prove significant differences comparing certain clinical data in familial and sporadic form of inflammatory bowel disease, yet males seem to be more prone to familial Crohn's disease. Small bowel was involved more often in familial form of Crohn's disease than in sporadic form.

Multicentre European study of thalamic stimulation for parkinsonian tremor: a 6 year follow-up.

AIM: To evaluate the results of ventral intermediate (Vim) thalamic deep brain stimulation (DBS) in patients with tremor predominant Parkinson's disease (PD) at 6 years post surgery. METHODS: This was a prolonged follow-up study of 38 patients from eight centres who participated in a multicentre study, the 1 year results of which have been published previously. Total scores as well as scores for individual items of the motor part and the disability part of the Unified Parkinson's Disease Rating Scale were used for evaluation. RESULTS: Tremor was still effectively controlled by DBS and appendicular rigidity and akinesia remained stable compared with baseline. Axial scores (speech, gait and postural instability), however, worsened, and in parallel the initial improvement in activities of daily living scores at the 1 year follow-up had disappeared at 6 years, despite sustained improvement of tremor. Remarkably, neither daily doses of dopaminergic medication nor fluctuations and dyskinesias had changed at 6 years compared with baseline in this particular patient group. CONCLUSION: This study confirms that patients with tremor dominant PD who do not present with fluctuations and dyskinesias may have a relatively benign progression of the disease. Vim DBS, although having no effect on akinesia and rigidity, is a relatively lenient surgical procedure and may still have a place for long term symptomatic control of PD tremor in selected patients.

[Significance of serum antibodies ANCA, ASCA, ABBA in diagnostics of idiopathic intestinal inflammations]. / Význam sérových protilátek ANCA, ASCA, ABBA u idiopatických strevních zánetu.

BACKGROUND: Crohn's disease and ulcerative colitis still remain a heterogeneous group of diseases with an unclear aetiology. Serologic methods play important role in their diagnosing though there is still not an ideal marker. We tried to determine the importance of serological testing of ASCA IgA, IgG, ANCA, ABBA antibodies in patients with ulcerative colitis and Crohn's disease. METHODS AND RESULTS: ASCA IgG, ASCA IgA; ANCA, ABBA antibodies and C-reactive protein were detected by indirect fluorescence assay. ASCA IgA, ASCA IgG, ABBA, ANCA were examined in 40 patients (28 Crohn's disease, 12 ulcerative colitis, 32 health controls). Specificity of ASCA IgA, IgG in CD patients was high (both 96.2%), specificity ANCA in UC 100%. ABBA antibodies had low sensitivity and specificity in both diseases. Combination of ASCA, ANCA, ABBA makes the specificity higher. CONCLUSIONS: We showed the importance of combination ASCA, ANCA with ABBA antibodies to improve the serological diagnosing of IBD.

[Importance of intrathecal pain therapy]. / Stellenwert der intrathekalen Schmerztherapie.

Intraspinal drug infusion using implantable pumps and catheter systems is a safe and effective therapy for selected pain patients with severe chronic pain. It improves pain relief, reduces drug-related side effects, decreases the need for oral analgesia and enhances quality of life in a segment of chronic pain patients whose pain has not been controlled with more conservative therapies. Intrathecal drug therapy has therefore established its role in the treatment of malignant pain, benign pain and severe spasticity.Careful patient selection and management as well as a multidisciplinary approach are determinants of successful treatment. Current practices for patient selection and management, screening, drug selection, dosing and implantation for intrathecal drug delivery systems are discussed.

Apomorphine test: a predictor for motor responsiveness to deep brain stimulation of the subthalamic nucleus.

The value of the apomorphine test as a predictor of the clinical outcome of deep brain stimulation of the subthalamic nucleus (STN) was evaluated in patients with advanced idiopathic Parkinson's disease (IPD) or multiple system atrophy (MSA). Thirteen IPD patients with severe diurnal fluctuations and one MSA patient not responding to dopaminergic drugs were assessed with the Unified Parkinson's Disease Rating Scale (UPDRS) and the timed finger tapping test (FTT), measured preoperatively on and off apomorphine and postoperatively on and off STN stimulation. UPDRS motor items 20-25 were assessed intraoperatively on and off STN stimulation when the clinically effective target was approached. The motor response to immediate intraoperative and long-term STN stimulation was correlated with results of the apomorphine test. The response to immediate intraoperative STN stimulation was accurately predicted by apomorphine challenge in all 13 IPD patients. Clinical outcome following long-term STN stimulation was correlated significantly with preoperative changes due to apomorphine measured with the UPDRS motor scores (r = 0.7125, P < 0.01) and FTT (r = 0.9276, P < 0.001). Moreover, comparison of long-term STN stimulation to preoperative drug treatment displayed a significant reduction in the duration of off-phases and a significant increase in the duration of on-phases. However, in the single patient with MSA no beneficial response was obtained either to apomorphine or to STN stimulation intraoperatively and during the postoperative externalized test period. Our results indicate that the apomorphine test can predict the outcome of immediate and long-term STN stimulation and may help in the selection of candidates for surgery.

Deep brain stimulation of the subthalamic nucleus for control of extrapyramidal features in advanced idiopathic parkinson's disease: one year follow-up.

UNLABELLED: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) with a quadripolar electrode was carried out in 9 patients with advanced idiopathic Parkinson's disease (PD) affected with severe diurnal motor fluctuations. The effect of bilateral STN stimulation was evaluated by clinical methods in all patients after 3 and 12 months. Assessment was based on the Unified Parkinson's Disease Rating Scale (UPDRS), timed motor tests, the Schwab and England Activities of Daily Living and a diary chart to document motor fluctuations. Alterations in parkinsonian signs, motor performance and functional outcome were recorded postoperatively (1) under temporary complete withdrawal of both STN stimulation and medication; (2) in the presence of STN stimulation only; and (3) in the presence of both STN stimulation and medication. The results were compared with the preoperative data assessed in defined on-phase and defined off-phase. STN stimulation on (compared to STN stimulation off) results in a significant improvement in UPDRS motor scores: after 3 months from 50.5 +/- 14.3 to 27.8 +/- 5.8, and after 12 months from 49.4 +/- 14.1 to 27.1 +/- 7.1 (p < 0.01). There was a significant decrease in the average duration of off-periods from 8.82 +/- 2.47 hours to 1.00 +/- 1.06 hours (p < 0.001), a marked increase in on-periods without dyskinesia from 4.62 +/- 2.72 to 14.62 +/- 1.51 hours (p < 0.01), and a sharp drop in on-periods with dyskinesia from 2.87 (+/- 4.18) to 0.25 (+/- 0.97) hours (p < 0.05), which remained stable up to 12 months (off-periods: 1.25 +/- 1.58 hours, p < 0.001; on-periods without: 13.87 +/- 1.95 hours, p < 0.001; and on-periods wth dyskinesia: 0.37 +/- 1.06 hours, p < 0.05). However, our first PD patient with an implanted DBS electrode within the STN died from cardiac infarction two days after surgery. This sudden death was not linked either to surgery nor to stimulation - and happened by chance. Our findings confirm that STN stimulation is a suitable functional neurosurgical procedure for the modulation and control of PD signs associated with severe motor fluctuations, in that they demonstrate a beneficial effect which was fully sustained over a one year follow-up period. KEYWORDS: Subthalamic nucleus, deep brain stimulation, Parkinson's disease.

Stimulation of the ventral intermediate thalamic nucleus in tremor dominated Parkinson's disease and essential tremor.

Based on Benabid's experimental and clinical findings that low-frequency (50 Hz) electrical stimulation of the ventral intermediate thalamic nucleus may increase tremor, while higher frequencies (> 100 Hz) lead to suppression of the tremor, we implanted a stimulation electrode in 33 thalami among 27 patients. Six patients were implanted bilaterally. 23 suffered from Parkinson's disease, 4 from essential tremor. All patients had a drug-resistant tremor. The Vim target was calculated based on stereotactic ventriculography. An intra-operative neurophysiological target control was performed on all patients. After a monopolar (12 thalami) or quadripolar (21 thalami) lead was implanted we then connected it to a percutaneous extension lead. In the days following the surgery a test stimulation was performed. In all but one patient stimulation resulted in a suppression of the tremor. In a second procedure, a pulse generator (ITREL II; MEDTRONIC) was implanted and connected subcutaneously to the thalamic lead. After implantation of the pulse generator all patients stimulate chronically while some turn off the stimulator at night. In 21 thalami total suppression of tremor was observed, 6 showed major improvement, 4 only minor improvement. There was no significant effect on any other existing symptom of Parkinson's disease. Due to the proximity of Vim to the sensory thalamus the majority of the patients (27 thalami) report slight temporary paraesthesias when the pulse generator is turned on. Two report permanent paraesthesias when stimulation is on. In 4 cases a slight dysarthria occurs under stimulation. In 2 the dysarthria is marked. In one case dysequilibrium occurs under stimulation. All these side effects are reversible when stimulation is turned off. In 3 patients, the lead was displaced due to an insufficient lead fixation, thus making a second procedure necessary to correct the electrode position. We had one complication due to bleeding at the burr hole side. Follow-up ranges from 3 to 48 months. So far in no cases has the effect of stimulation worn off. In conclusion we regard Vim neurostimulation as an effective and safe alternative to conventional thalamotomy and recommend that it should be considered in cases in which drug therapy has failed to affect Parkinsonian or essential tremor. Moreover, we believe that this procedure is a less invasive and equally efficient alternative to classic thalamotomy and thus should be given preference.

Calpeptin, a calpain inhibitor, promotes neurite elongation in differentiating PC12 cells.

Calpain activity of nerve growth factor (NGF)-induced rat pheochromocytoma (PC12) cells shows a transient diminution in the early phase of differentiation. Calpain activity can be further decreased by a cell-permeable calpain inhibitor, calpeptin, which enhances the effect of NGF by stimulating neurite elongation. The number of neurites sprouted by one cell is not increased by calpeptin. A possible role of calpain inhibition during PC12 cells' early differentiation is discussed.

Purification and characterization of a Ca(2+)-activated thiol protease from Drosophila melanogaster.

A Ca(2+)-activated thiol protease was purified from Drosophila melanogaster. The procedure involves Phenyl-Sepharose, Reactive Red-Agarose and Q-Sepharose fast flow (or MonoQ) chromatographic steps. The enzyme eluting from Q-Sepharose fast flow seems to be homogeneous as judged by silver staining on SDS-PAGE: it consists of a single polypeptide chain of M(r),app = 94K and pI = 5.46. The proteolytic activity of the purified enzyme is absolutely Ca(2+)-dependent, characterized by 0.6 mM free Ca2+ at half-maximal activity. Ca2+ ions cannot be replaced effectively by the divalent cations Mg2+, Mn2+, Zn2+, Ba2+, and Cd2+. The enzyme shows the inhibitor pattern of thiol proteases. Human recombinant calpastatin (domain I) completely inhibits the enzyme at a nearly 1:1 molar ratio. Several of these properties resemble those of vertebrate calpain II. However, various attempts to detect a small subunit of M(r) approximately 30K, common with vertebrate calpains, remained unsuccessful. We suggest that the Drosophila enzyme is a novel calpain II-like protease.

Altered autophosphorylation of adenosine 3',5'-phosphate-dependent protein kinase in the dunce memory mutant of Drosophila melanogaster.

The phosphorylation-dephosphorylation, in the presence of adenosine 5'-[gamma-32P]triphosphate, of a polypeptide of apparent molecular mass 53,000 has been compared in head homogenates of wild type and memory mutant dunceM11 strains of Drosophila melanogaster. In both strains, labelling of the 53 kilodalton protein required exogenous adenosine 3',5'-phosphate (cAMP), but in dunceM11 cAMP at higher concentration (above approximately 3 microM) caused the rapid disappearance of the label. This differential dephosphorylation can be attributed to the lack of a cAMP-specific phosphodiesterase isoenzyme in the mutant. Several lines of evidence indicate that the 53 kilodalton protein is identical with the regulatory subunit of cAMP-dependent protein kinase. The findings suggest that in the mutant's nerve cells the state of phosphorylation of the regulatory subunit of cAMP-dependent protein kinase is altered, which may contribute to the biochemical disorder leading to the memory deficit.